Tumor necrosis factor (
TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF super-family, and it has been shown that many human
cancer cell lines are refractory to TRAIL-induced cell death. However, the molecular mechanisms underlying resistance are unclear. In the present study, we show that TRAIL-resistance is reversed in human
hepatoma cells by
anisomycin, which is known to inhibit
protein synthesis and induce ribotoxic stress. Synergistic induction of apoptosis in cells treated with
anisomycin plus TRAIL was associated with activation of
caspases and cleavage of Bid, a pro-apoptotic BH3-only
protein. Silencing of Bid expression by
small interfering RNA (
siRNA) significantly attenuated the loss of mitochondrial membrane potential (
MMP, Δψm) and significantly increased induction of apoptosis in cells treated with
anisomycin and TRAIL, confirming that Bid cleavage is required for the response. In addition, c-Jun/AP-1 was rapidly activated upon stimulation with
anisomycin; however, the knockdown of c-Jun/AP-1 expression by c-Jun
siRNA markedly reduced
anisomycin plus TRAIL-induced loss of
MMP and apoptosis. Taken together, the findings show that
anisomycin sensitizes TRAIL-mediated
hepatoma cell apoptosis via the mitochondria-associated pathway, involving the cleavage of Bid and activation of the c-Jun/AP-1 pathway, indicating that this compound can be used as an anti-
tumor agent in combination with TRAIL.